PRIOR ART
This invention relates to the manufacture of 8-methoxypsoralen and is directed to improvements in a process in which pyrogallol is converted to 8-methoxypsoralen in six unit process steps.
Lagercrantz, Acta Chemica Scandinavica Vol. 10, (1956) pp. 647-654 reports the preparation of 8-methoxypsoralen in the following six unit process steps beginning with pyrogallol:
(1) Pyrogallol is reacted with chloracetic acid in the presence of phosphorus oxychloride to form .omega.-chloro-2,3,4-trihydroxyacetophenone, PA1 (2) which product is cyclized by the splitting off .[.hydrochloric acid.]. .Iadd.of hydrogen chloride .Iaddend.to form 6,7-dihydroxycoumaranone, PA1 (3) which product is hydrogenated with hydrogen over a palladium catalyst in acetic acid at 1 atmosphere and 65.degree. C. .[.,.]. .Iadd.to form 6,7-dihydroxy-2,3-dihydrobenzofuran, .Iaddend. PA1 (4) which product is reacted with malic acid in the presence of concentrated sulphuric acid to form .Badd..[.2,3-dihydroxanthotoxol.]..Baddend. .Iadd.4',5'-dihydroxanthotoxol, .Iaddend. PA1 (5) which product is methylated using diazomethane to form .Badd..[.2,3-dihydroxanthotoxin.]..Baddend. .Iadd.4',5'-dihydroxanthotoxin, .Iaddend. PA1 (6) which product is dehydrogenated with palladium catalyst in boiling diphenyl ether to form the desired 8-methoxypsoralen (xanthotoxin). PA1 (1) reacting pyrogallol with chloracetic acid to form .omega.-chloro-2,3,4-trihydroxyacetophenone, PA1 (2) heating .omega.-chloro-2,3,4-trihydroxyacetophenone in the presence of a hydrogen chloride acceptor to form 6,7-dihydroxycoumaranone, PA1 (3) hydrogenating 6,7-dihydroxycoumaranone to form 6,7-dihydroxy-2,3,-dihydrobenzofuran, PA1 (4) reacting 6,7-dihydroxy-2,3,-dihydrobenzofuran with malic acid to form .Badd..[.2,3-dihydroxanthotoxol.]..Baddend. .Iadd.4',5'-dihydroxanthotoxol, .Iaddend. PA1 (5-6) methylating and dehydrogenating to convert .Badd..[.2,3-dihydroxanthotoxol.]. .Iadd.4',5'-dihydroxanthotoxol .Iaddend.to 8-methoxypsoralen,
Davies et al., J. Chem. Soc., (1950), 3202-6 reports the first two of these unit process steps and Spath et al., Ber. 69, (1936), 767-770, reports the last four of these steps.
The overall yield in these prior art processes is less than about 3 percent. This is due to the relatively low yield in some or most of the unit process steps. The problem steps apparently are the hydrogenation step (3) and the dehydrogenation step (6). In regard to the former, Spath obtained 33 percent yield and Lagercrantz, 50 percent yield. However, Lagercrantz points out that this unit process is highly critical, that the hydrogenation also involves enolization of the oxo group and that the starting 6,7-dihydroxycoumaran-3-one (hereinafter referred to as 6,7-dihydroxycoumaranone) must be "very pure" in order to avoid poisoning of the catalyst. He suggests recrystallization several times with active carbon. In regard to the dehydrogenation, the best yield reported is 37 percent. This, coupled with the relatively low yields reported for steps 1, 3, and 4, makes the overall yield of the prior art process less than about 3 percent.